Women are prone to develop chronic, often severe, consequences as a result of cervical infection with Neisseria gonorrhoeae. Although clinical data indicate that there is a hormonal component to gonococcal infection in women, this avenue of study has received little attention. Our data are consistent with this idea and demonstrate distinct roles for estrogen (E2) and progesterone (Pg) in modulating gonococcal infection of cervical epithelia. The objective of this proposal is to define the role of steroid hormone receptors (SHRs) in the response(s) of primary cervical epithelia to gonococal infection under physiological concentrations of E2 and Pg. Our previous data suggest that the asymptomatic nature of gonococcal cervicitis may, in part, be attributed to the ability of gonococci to subvert the normal function of the alternative pathway of complement (C') in such a way to promote invasion via complement receptor 3 (CR3). However, it is also noteworthy that steroid hormones (SHs) exert anti-inflammatory properties, which are, in part, attributed to the ability of their cognate cellular receptors, to function as transcription factors and/or to modulate signaling cascades triggered with cell stimulation. In this regard, SHRs are shown to regulate the expression of some C'proteins. One unique aspect of this proposal relates to the clinical relevance of our use of primary human cervical epithelial (pex) cells to study gonococcal disease of women. CR3 is the primary receptor exploited by N. gonorrhoeae, in vivo and ex vivo, to associate with and invade the cervix. Although CR3 is present on pex cells, it is not present on the epithelium of the (human) male urogenital tract, the mouse female genital tract, nor immortalized/malignant cervical cell lines. Therefore, by using pex cells as a model of the lower female genital tract, we have been able to reveal aspects of N. gonorrhoeae pathogenesis that are specific to infection of women and that have been over-looked by the use of other model systems. We are the only laboratory routinely using primary human epithelial cells to study gonococcal pathogenesis. Additionally, recent data indicate that SHR expression is absent or severely down regulated in immortalized/malignant cervical epithelia, making immortal cell lines of limited utility in elucidation of SHR function. Thus we are uniquely suited to provide a detailed analysis of the affect of SHs on cervical biology and gonococcal pathogenesis. PUBLIC HEALTH RELEVANCE: The focus of this application is to define the effect(s) of steroid hormones on primary cervical epithelia and, thereby, the effect on asymptomatic gonococcal cervicitis. The proposed studies are an important and under-investigated area of bacterial pathogenesis and are directly applicable to the human health.